BE1000946A3 - New p-chloro-N-morpholino-propyl-benzamide(s) and hydrochloride(s) - have antidepressant and psycho stimulant activity - Google Patents

Abstract

Novel p-chloro N-(3-morpholino-propyl)-benzamide cpds. and their hydrochlorides have formula (1); where X shows in this case the presence of a hydrochloride-, are prepd. in a polar solvent which prevents the formation of by-products.

Description

       

    <Desc / Clms Page number 1>
 
 EMI1.1
 



  "Para-chloro-N-O-morpholinopropyl) benzamide, its hydrochloride, its preparation process and anti-depressant and psychostimulatory drug based on this substance's hydrochloride".



   The present invention relates to organic chemistry, and more specifically parachloro-N- (3-morpholinopropyl) benzamide, its hydrochloride, a process for their preparation and a medicament, with antidepressant and psychostimulatory action based on hydrochloride of this substance, finding application in medicine for the treatment of depressions of various etiologies.



   We know drugs with antidepressant activity, such as Imipramine,
 EMI1.2
 Chlorimipramine, Pirlindol, Desmethylimipramine, etc. (M. D. Mashkovsky, Lekarstvennye sredstva, Moscow, Eds. Meditsina 1977). All the drugs indicated are characterized by a limited spectrum of action and the manifestation of side effects.



   We know the para-chloro-N- (2-morpholino-ethyl) benzamide compound of formula:
 EMI1.3
 which has antidepressive activity (it is
 EMI1.4
 the drug Mociobemide).



   The antidepressant activity of this compound is based on its property of inhibiting the monoamine oxidase of the liver, which limits the field of its application. In addition, this compound is toxic. The process for the preparation of said compound consists in reacting the chloride of

  <Desc / Clms Page number 2>

 para-chlorobenzoyl and N- (2-amino-ethyl) mopholine within pyridine or ethyl ether. In the first case, the reaction mass is reduced by evaporation, the residue is removed twice with toluene, then it is treated with an alkali and extracted with an organic solvent. The organic solution is washed with water, dried and evaporated.

   Parachloro-N- (2-morpholino-ethyl) benzamide with a fuse point of 137OC is obtained. In the second case, the product isolated from the ester solution is recrystallized from isopropanol and the hydrochloride of the indicated compound is obtained (30% by mass) (German patent application A 2,706,179).



   The process in question is characterized by a low yield of the target product due to the formation of side reaction products as well as by an inconvenient execution of the process in the presence of a toxic solvent (pyridine). This process has not found industrial use.



   The compounds claimed in the present invention are new and have not been described in the literature.



   It has therefore been proposed to prepare new compounds having a high antidepressant and psychostimulatory activity, a broad spectrum of action and a low toxicity, as well as to develop a technology for the simplified preparation of these substances.



   In accordance with the invention, the new compounds, in particular para-chloro-N- (3-morpholinopropyl) benzamide and its hydrochloride correspond to the general formula:

  <Desc / Clms Page number 3>

 
 EMI3.1
 which X represents HCl or is absent.



   The process for preparing para-chloro-N- (3-morpholinopropyl) benzamide and its hydrochloride, according to the invention, consists in reacting N- (3-aminopropyl) morpholine and para-chlorobenzoyl chloride within of a polar organic solvent, inhibiting the formation of secondary reaction products
 EMI3.2
 res, then isolate the target product.



   As polar organic solvent, ethanol, isopropanol, chloroform, acetone, dichloroethane, methylene chloride or acetonitrile are preferably used.



   As a result of the reaction, para-chloro-N- (3-morpholinopropyl) benzamide hydrochloride is formed, isolated and recrystallized from an organic solvent in order to purify it.



   To prepare para-chloro-N- (3-morpholinopropyl) benzamide (base), the para-chloro-N- (3-morpholinopropyl) benzamide hydrochloride is reacted with an alkali in an aqueous medium.



   The claimed compounds have antidepressant and psychostimulatory activity, they are not toxic.



   The medicament according to the invention, with antidepressant and psychostimulatory action, containing an active principle and a pharmaceutical excipient, contains, as active substance, para-chloro hydrochloride N- (3-morpholinopropyl) benzamide of formula:
 EMI3.3
 

  <Desc / Clms Page number 4>

 
 EMI4.1
 The drug can be applied in various dosage forms; the claimed drug is preferably used in the form of injectable solutions and tablets.



  The medicament in the form of injections preferably contains the active substance in an amount of 0.25% by mass and as a pharmaceutical excipient, it preferably contains as solvent bidistilled water.



  The medicament claimed in tablet form preferably contains the active substance in an amount of 0.01 g per tablet, and as a pharmaceutical excipient, starch or powdered sugar.



  The claimed drug is more effective than Moclobemide for the treatment of a wide range of depressions of various severities, has individual features of the spectrum of psychotropic activity, it has a broad spectrum of therapeutic action, a very early onset of action. fast and longer action.



  The claimed drug has a high antiarrhythmic activity, it is effective in patients in alcoholic remission and outside the period of acute abstinence. It can also be recommended for the treatment of psychosuppressive disorders in gerontological and infantile practices as well as during the development of exorbitant fatigue.



  The claimed drug, alongside the serotonergic component, has a marked dopaminergic component, which is lacking in Moclobemide.

  <Desc / Clms Page number 5>

 



  The process for preparing the claimed compounds is carried out as follows:
Parachloro-benzoyl chloride and N- (3-aminopropyl) morpholine are reacted in a polar organic solvent, inhibiting the formation of
 EMI5.1
 side reactions. Ethanol, isopropanol, acetone, dichloroethane, methylene chloride or acetonitrile are used as the polar organic solvent.



  The reaction provides para-chloro-N- (3-morpholinopropyl) benzamide hydrochloride which is filtered and recrystallized. A product with a melting point of 188-189OC is obtained, which is a white crystalline substance, well soluble in water, ethyl alcohol, acetone.



   To isolate para-chloro-N (3-morpholinopropyl) benzamide, the para-chloro-N- (morphorpholinopropyl) benzamide hydrochloride obtained is treated with an aqueous alkali solution, the base obtained is extracted with an organic solvent , drying, removing the solvent and obtaining a product with a melting point of 87-88OC, which is a white crystalline substance, soluble in acetone, ethanol, chloroform, hardly soluble in water.



   The process indicated avoids the formation of side reaction products and increases the yield of targeted products up to 97% by mass.

  <Desc / Clms Page number 6>

 



   The antidepressant and psychostimulatory activity of the claimed compounds has been studied experimentally in animals and in humans in clinics.



   During detailed pharmacological studies carried out on suitable models of behavioral pathology (oppression, depression) in animals (dogs, cats, rats, mice) during a single, repeated administration (double and prolonged for 7 to 14 days) , the claimed compounds [para-chloro-N- (3-morpholinopropyl) benzamide and its hydrochloride have been shown to be highly active compounds that suppress depression (the duration of administration depended on the severity of the medical condition) .

   The claimed compounds have an individual spectrum of psychotropic activity which distinguishes them from known antidepressants from the group of tricyclic compounds (Imipramine, Desmethylimipramine, Amitryptiline), monoamine oxidase inhibitors (Nialamide, Nuredal) and also atypical antidepressants (Viloxazine, Befuralin, Mianserine).



   The acute and chronic toxicity of the claimed compounds was studied: para-chloro-N- (3-morpholinopropyl) benzamide (base) and its hydrochloride. The acute toxicity of 50 in rats after oral administration is: 4000 mg / kg of the animal weight for the base and 5000 mg / kg for the hydrochloride
The claimed compounds were administered for 6 months to animals internally at the doses: 1 mg / kg, 50 mg / kg, 300

  <Desc / Clms Page number 7>

 
 EMI7.1
 mg / kg (1/16 of the Dol50) for rats and 50 mg / kg for guinea pigs and 50 mg / kg for dogs.



   The general condition and behavior of the animals according to the observation results did not differ from those of the control animals.



   The claimed compounds were administered to 6 rabbits for 30 days at doses of 5 mg / kg: intravenously drip (as 0.025% solution) for 10 days, intramuscularly for 10 days and orally for 10 days. Observations showed that the general condition of 5 rabbits was indistinguishable from the general condition of the controls, one rabbit showing symptoms of a cerebral circulation disorder.



   Trials have been performed on a type of behavioral depression in cats.



  Prolonged depression (more than 7 days) developed in cats after administration of Reserpine (0.1 mg / kg) or after reiterative electrocutaneous irritation (conflict situation, fear). After administration of the claimed compound (para-chloro-N- (3-morpholino-propyl) benzamide hydrochloride at a single dose of 0.5-1 mg / kg, all manifestations of depression were eliminated by 3rd day of treatment Elimination of overwhelming (asthenia), inhibition, restitution of motivational activity, adequate emotional reaction and assessment of the situation were the main manifestations in the

  <Desc / Clms Page number 8>

 development of the antidepressant effect.

   The claimed compound has also led to the elimination of somatovegetative dysfunctions (motor activity has recovered, catalepsy has diminished, temperature homeostasis has recovered, etc.). The elimination of fear, the restitution of activity oriented behavior were the main factors in the development of antidepressant action on the model of reactive depression.



   Neurochemical studies carried out on the same animals have shown that the anti-depressant effect of the claimed compound on the behavioral Reserpine depression model has been correlated with the normalization of the state of the dopaminergic and serotonergic systems of the brain. and, to a lesser extent, the noradrenergic system.



   The results of the tests are summarized in Table 1.

  <Desc / Clms Page number 9>

 



   Table 1 Individual differences in the action of known anti-depressants and of the claimed compound on certain manifestations of the behavioral depression complex caused by Reserpine in cats
 EMI9.1
 
 <tb>
 <tb> Depression <SEP> from
 <tb> NN <SEP> Events <SEP> Standard <SEP> behavior
 <tb> 1 <SEP> 2 <SEP> 3 <SEP> 4
 <tb> 1 <SEP> Aggression <SEP> 2, <SEP> 7-2, <SEP> 6
 <tb> 2 <SEP> Fear <SEP> 2, <SEP> 6-2, <SEP> 4
 <tb> 3 <SEP> Conflict <SEP> 2, <SEP> 7-2, <SEP> 3
 <tb> 4 <SEP> Negativity <SEP> 2, <SEP> 9-2, <SEP> 5
 <tb> 5 <SEP> Pleasure <SEP> 2, <SEP> 2-2, <SEP> 6
 <tb> 6 <SEP> Benevolence <SEP> 2, <SEP> 1-1, <SEP> 9
 <tb> 7 <SEP> Hunting <SEP> 2, <SEP> 2-2, <SEP> 6
 <tb> 8 <SEP> Activity <SEP> from <SEP> search <SEP> 2, <SEP> 5-3, <SEP> 1
 <tb> 9 <SEP> Behavior <SEP> food <SEP> 1, <SEP> 8-2,

    <SEP> 2
 <tb> 10 <SEP> Exhaust <SEP> to <SEP> actions <SEP> dislike <SEP> 1, <SEP> 5-1, <SEP> 9
 <tb> 11 <SEP> Activity <SEP> motor <SEP> spontaneous <SEP> 3, <SEP> 2-2, <SEP> 5
 <tb> 12 <SEP> Catalepsy - ++
 <tb> 13 <SEP> Miose <SEP> - <SEP> ++
 <tb> 14 <SEP> Ptose - ++
 <tb>
 

  <Desc / Clms Page number 10>

 
 EMI10.1
 Antidepressants
 EMI10.2
 
 <tb>
 <tb> Compound <SEP> From <SEP> sméNN <SEP> claimed- <SEP> thylimi- <SEP> Nia- <SEP> Pir- <SEP> Vilo- <SEP> Befuqué <SEP> pramine <SEP> lanide <SEP> lindol <SEP> xazine <SEP> raline
 <tb> 1 <SEP> 5 <SEP> 6 <SEP> 7 <SEP> 8 <SEP> 9 <SEP> 10
 <tb> 1 <SEP> -2.6 <SEP> 2.4 <SEP> 2.2 <SEP> -1.8 <SEP> 1.3 <SEP> -1.7
 <tb> 2 <SEP> -2.4 <SEP> 1.7 <SEP> 1.9 <SEP> -2.2 <SEP> 2.1 <SEP> -2.3
 <tb> 3 <SEP> -2.2 <SEP> 1.9 <SEP> 2.1 <SEP> -2.1 <SEP> 0.6 <SEP> -1.9
 <tb> 4 <SEP> -3.0 <SEP> -2.2 <SEP> -2.4 <SEP> 2.2 <SEP> 1.9 <SEP> 2,

  4
 <tb> 5 <SEP> - <SEP> 1.6 <SEP> -1.4 <SEP> 2.0 <SEP> 2.6 <SEP> 1.4 <SEP> 2.7
 <tb> 6 <SEP> 2, <SEP> 3-1, <SEP> 8-1, <SEP> 9 <SEP> 2, <SEP> 7 <SEP> 1, <SEP> 1 <SEP> 0, <SEP> 5
 <tb> 7 <SEP> 2, <SEP> 2-1, <SEP> 2-1, <SEP> 7 <SEP> 1, <SEP> 3 <SEP> 1, <SEP> 6 <SEP> 1, <SEP> 4
 <tb> 8 <SEP> 1, <SEP> 7 <SEP> -2.0 <SEP> -2.1 <SEP> 2.0 <SEP> 1.6 <SEP> 2.1
 <tb> 9 <SEP> 3, <SEP> 4 <SEP> -2.0 <SEP> -2.1 <SEP> 1.8 <SEP> 2.2 <SEP> 3.0
 <tb> 10 <SEP> 2, <SEP> 4-2, <SEP> 0-1, <SEP> 8 <SEP> 1, <SEP> 9 <SEP> 2, <SEP> 1 <SEP> 1, <SEP> 9
 <tb> 11 <SEP> 3, <SEP> 0 <SEP> 1, <SEP> 1 <SEP> 1, <SEP> 6 <SEP> 0, <SEP> 9 <SEP> 1, <SEP> 4 <SEP> 1, <SEP> 9
 <tb> 12 <SEP> + - ++ <SEP> + - + -
 <tb> 13 <SEP> ++ - + - +
 <tb> 14 <SEP> + - + -
 <tb> + -The <SEP> searches <SEP> from <SEP> activity
 <tb>
 
 EMI10.3
 antidepressants were carried out according to the test of the swimming test (method of Porsolt et al. 1977).

   A single administration of the compound claimed in this model has definitely reduced the immobilization time of mice subjected to forced swimming in a closed space. Administration of the claimed compound at a dose of 1 mg / kg for two weeks and tests carried out on mice according to this method 24 hours after the last administration have shown the conservation and

  <Desc / Clms Page number 11>

 reinforcement of the antidepressant effect following the swimming test. The efficacy of the claimed compound surpassed a series of known antidepressants. The results of the study are summarized in Table 2.

  <Desc / Clms Page number 12>

 



   Table 2 Effect of the single administration of the claimed compound and of various known antidepressants on the behavior of mice under the swimming test conditions
 EMI12.1
 
 <tb>
 <tb> Subs- <SEP> Doses <SEP> Duration <SEP> medium <SEP> Percentage
 <tb> NN <SEP> tances <SEP> in <SEP> mg / kg <SEP> of fixed assets <SEP> deviation <SEP> by
 <tb> tion <SEP> (dry) <SEP> report <SEP> to
 <tb> cookies
 <tb> 1 <SEP> 2 <SEP> 3 <SEP> 4 <SEP> 5
 <tb> 1 <SEP> Compound <SEP> Witnesses <SEP> 233
 <tb> 2 <SEP> resell.

    <SEP> 5.0 <SEP> 138¯17 ** <SEP> -41
 <tb> 3 <SEP> 1, <SEP> 0 <SEP> 120 + 13 ** - 48
 <tb> 4 <SEP> 0, <SEP> 5 <SEP> 111t15 ** <SEP> -52
 <tb> 5 <SEP> 0, <SEP> 1 <SEP> 118 + 12 ** - 49
 <tb> 6 <SEP> Moclo- <SEP> Witnesses <SEP> 133¯4 <SEP> -
 <tb> 7 <SEP> bemide <SEP> 5.0 <SEP> 72¯ <SEP> 5 ** <SEP> -46
 <tb> 8 <SEP> 1.0 <SEP> 89¯12 ** <SEP> -38
 <tb> 9 <SEP> 0, <SEP> 5 <SEP> lOOt <SEP> 8 ** - 25
 <tb> 10 <SEP> 0, <SEP> 1 <SEP> 117 + 13-13
 <tb> 11 <SEP> Pirlin- <SEP> Witnesses <SEP> 203¯7
 <tb> 12 <SEP> dol <SEP> 25, <SEP> 0 <SEP> 169 + 10 * -17
 <tb> 13 <SEP> 10, <SEP> 0 <SEP> 147 + 19 * -28
 <tb> 14 <SEP> 5, <SEP> 0 <SEP> 168 + 14 * -17
 <tb> 15 <SEP> 1, <SEP> 0 <SEP> 179 + 17-12
 <tb>
 

  <Desc / Clms Page number 13>

 Continued Table 2
 EMI13.1
 
 <tb>
 <tb> 16 <SEP> Chlori- <SEP> Witnesses <SEP> 208 + 14 <SEP> -
 <tb> 17 <SEP> mipramine <SEP> 10, <SEP> 0 <SEP> 99.

    <SEP> t19 ** <SEP> -52
 <tb> 18 <SEP> 5, <SEP> 0 <SEP> 111 + 11 ** - 47
 <tb> 19 <SEP> 1, <SEP> 0 <SEP> 154 + 15 * -26
 <tb>
 
 EMI13.2
 * and ** significant differences with respect to controls when P {. 0.05 and P 0.01 respectively.



   The study of the antidepressant effect during prolonged use of the claimed compound was carried out according to the "learned helplessness" method (Anisman method).



   The learned impotence is based on the fact that the mice and the rats, after having undergone an inevitable previous electrocutaneous irritation, show a considerable deficit in the behavior of the exhaust in the "shuttle chamber". This form of behavioral depression persisted in animals for two weeks. The single administration of antidepressants of various groups has no influence on the indices of behavior. However, the claimed compound considerably reduces the average latency of the escape period in mice.



   Administration of the claimed compound during
7 days brought about essential changes in animal behavior. After administration of the claimed compound for
14 days, animals completed the escape reaction like animals

  <Desc / Clms Page number 14>

 witnesses. The effect of administering the claimed compound for 14 days was similar to that of the tricyclic antidepressants.



  However, as tests have shown, the antidepressant activity of the claimed compound has already manifested itself with a single administration, and the complete elimination of behavioral depression has developed on this model at the 5-7th day. The results of the studies are summarized in Table 3.

  <Desc / Clms Page number 15>

 



   Table 3 Effect of single and repetitive administrations of the claimed compound on the indices of the escape reaction in mice subjected to an inevitable prior stressful action according to the "dimpississeapprise" model by comparison with similar administrations of known antidepressants
 EMI15.1
 
 <tb>
 <tb> Percent <SEP> escape <SEP> Latency
 <tb> NN <SEP> Substances <SEP> pement <SEP> from <SEP> number <SEP> medium <SEP> from <SEP> the
 <tb> (mg / kg) <SEP> total <SEP> of tests <SEP> period
 <tb> exhaust
 <tb> M + m <SEP> (dry)
 <tb> 1 <SEP> 2 <SEP> 3 <SEP> 4
 <tb> Administration <SEP> single
 <tb> 1 <SEP> Witness-1 <SEP> 10 <SEP> 4.1¯0.3
 <tb> 2 <SEP> Witness-2 <SEP> 51 <SEP> 10, <SEP> 0 + 0, <SEP> 7
 <tb> 3 <SEP> Compound
 <tb> claims
 <tb> (1, <SEP> 0) <SEP> ++ 40 <SEP> 4, <SEP> 3 + 0, <SEP> 9 **
 <tb> 4 <SEP> Pirlindol
 <tb> (10,

    <SEP> 0) <SEP> ++ 38 <SEP> 5, <SEP> 5 + 0, <SEP> 6 **
 <tb> 5 <SEP> Desipramine
 <tb> (10, <SEP> 0) <SEP> +34 <SEP> ++ 7, <SEP> 0 + 0, <SEP> 4 *
 <tb>
 

  <Desc / Clms Page number 16>

 Continued Table 3
 EMI16.1
 
 <tb>
 <tb> Administration <SEP> during <SEP> 7 <SEP> days
 <tb> 6 <SEP> Witness-1 <SEP> 11 <SEP> 5, <SEP> 9 + 0, <SEP> 4
 <tb> 7 <SEP> Witness-2 <SEP> 59 <SEP> 11, <SEP> 1 + 0, <SEP> 8
 <tb> 8 <SEP> Compound
 <tb> claims <SEP> 24 ** <SEP> 6, <SEP> 90, <SEP> 4 **
 <tb> 9 <SEP> Pirlindol <SEP> 13 ** <SEP> 7, <SEP> 30, <SEP> 6 **
 <tb> 10 <SEP> Desipramine <SEP> ++ 31 * <SEP> 7, <SEP> 8 <SEP>:

    <SEP> t0, <SEP> 4 **
 <tb> Administration <SEP> during <SEP> 14 <SEP> days
 <tb> 11 <SEP> Witness-1 <SEP> 16 <SEP> 5.8¯0.4
 <tb> 12 <SEP> Witness-2 <SEP> 59 <SEP> 10, <SEP> 6 + 0, <SEP> 9
 <tb> 13 <SEP> Compound
 <tb> claimed <SEP> 14 ** <SEP> 5, <SEP> 4 + 0, <SEP> 5 **
 <tb> 14 <SEP> Pirlindol <SEP> 16 ** <SEP> 5, <SEP> 30, <SEP> 9 **
 <tb> 15 <SEP> Desipramine <SEP> 18 ** <SEP> +7, <SEP> 1 + 0, <SEP> 4 **
 <tb>
   + P # 0.05; ++ P # 0.01 compared to control-1 (intact mice) * P # 0.05;

   ** P # 0.01 compared to control-2
 EMI16.2
 (stressed mice)
Similarly, behavioral tests carried out on suitable models of behavioral pathology have shown that after two administrations of the claimed compound, the onset of curative action has already been observed in cats, mice and rats . The complete elimination of behavioral depression, depending on the severity of the

  <Desc / Clms Page number 17>

 cloudy, occurred on 3-5 days of administration of the claimed compound to animals.



   The effect of the claimed compound on
 EMI17.1
 Actions of 5-oxytryptophan has been studied using the "head shake" method in mice. the claimed compound potentiated the action of 5-oxytryptophan. This effect was more marked than that observed after administration of Chlorimipramine and Pirlindol. The potentiation effect increased considerably after the administration of antidepressants for two weeks. The results of the tests are presented in Table 4.

  <Desc / Clms Page number 18>

 



   Table 4 Effect of the claimed compound on the phenomenon of "head shaking 11 in mice caused by the ingestion of 5-oxytryptophan at the dose of 180 mg / kg
 EMI18.1
 
 <tb>
 <tb> Number <SEP> from <SEP> shakes <SEP> from <SEP> the <SEP> head
 <tb> M + m
 <tb> MN <SEP> Substances <SEP> ---------------------------------
 <tb> (mg / kg) <SEP> administration <SEP> administration
 <tb> unique <SEP> during <SEP> 14 <SEP> days
 <tb> 1 <SEP> 2 <SEP> 3 <SEP> 4
 <tb> 1 <SEP> Witness <SEP> 20, <SEP> 30, <SEP> 9 <SEP> 20, <SEP> 0 + 3, <SEP> 4
 <tb> 2 <SEP> Compound
 <tb> claims
 <tb> (1.0) <SEP> 31.2¯3.7 * <SEP> 56.2¯5.9 **
 <tb> 3 <SEP> Chlorimipramine
 <tb> (10, <SEP> 0) <SEP> 27.2¯1.9 * <SEP> 30.8¯3.8 *
 <tb> 4 <SEP> Pirlindol
 <tb> (10, <SEP> 0) <SEP> 28.2¯2.6 <SEP> 34.2¯3,

  4 *
 <tb>
 * and ** - significant differences in control for P # 0.05 and P # 0.01 respectively.



   Tests carried out on simpler behavioral models and on models characterizing the pharmacological properties have shown that the compound claimed from the initial effective dose of 0.5 mg / kg up to 70 mg / kg

  <Desc / Clms Page number 19>

 did not disturb the coordination of movements; At the 100 mg / kg dose it caused insignificant changes (in 25% of animals) and it was only at the 200 mg / kg dose that coordination was disturbed.



   The claimed compound has no influence on the body temperature, while Pirlindol has lowered the temperature of the
 EMI19.1
 body in mice like also Imipramine.



  The study of the action on the cerebral bioelectric activity of rats and cats has shown that the claimed compound causes an increase in slow activity in the electrograms of the cortical and septal regions of the brain of rats. The claimed compound causes an increase in the theta rhythm of the hypocampus with a simultaneous reinforcement of the beta activity, which testifies to the activating effect of the substance on the
 EMI19.2
 desynchronizing reticulo-hypothalamic structures of the brain. The comparison of these data with the results of the study of tricyclic antidepressants and known atypical antidepressants revealed a peculiarity of the action of the claimed compound on the bioelectrical activity of the brain.



   The influence of the claimed compound on the learning process under the conditions of the passive escape method has been studied. The claimed compound was administered at doses of 0.5 mg / kg and 5 mg / kg. The claimed compound significantly improves the animals' ability to memorize in situ.

   The results are summarized in Table 5

  <Desc / Clms Page number 20>

 
Table 5 Effect of the claimed compound on the learning process under the conditions of the passive escape method in mice
 EMI20.1
 
 <tb>
 <tb> Reflex <SEP> orientation <SEP> next <SEP> ap- <SEP> Reproduction <SEP> after
 <tb> learning <SEP> 48 <SEP> hours
 <tb> NN <SEP> NN <SEP> of
 <tb> mouse <SEP> time <SEP> from <SEP> time <SEP> from <SEP> period <SEP> time <SEP> from <SEP> time <SEP> from
 <tb> stay <SEP> stay Latent <SEP> <SEP> from <SEP> stay <SEP> stay
 <tb> in <SEP> the <SEP> in <SEP> the <SEP> the <SEP> visit <SEP> in <SEP> the <SEP> in <SEP> the
 <tb> room <SEP> room <SEP> in <SEP> the <SEP> room <SEP> room
 <tb> clear <SEP> black <SEP> room <SEP> clear <SEP> black
 <tb> (seconds) <SEP> (seconds)

    <SEP> (seconds) <SEP> (seconds) <SEP> (seconds)
 <tb> 1 <SEP> 2 <SEP> 3 <SEP> 4 <SEP> 5 <SEP> 6 <SEP> 7
 <tb> Animals <SEP> Witnesses
 <tb> 1 <SEP> 1 <SEP> 70 <SEP> 50 <SEP> 5 <SEP> 60 <SEP> 60
 <tb> 2 <SEP> 2 <SEP> 60 <SEP> 60 <SEP> 105 <SEP> 105 <SEP> 15
 <tb> 3 <SEP> 3 <SEP> 40 <SEP> 80 <SEP> 120 <SEP> 120 <SEP> 0
 <tb> 4 <SEP> 4 <SEP> 40 <SEP> 80 <SEP> 15 <SEP> 20 <SEP> 100
 <tb> 5 <SEP> 5 <SEP> 20 <SEP> 100 <SEP> 30 <SEP> 110 <SEP> 10
 <tb> 6 <SEP> 6 <SEP> 10 <SEP> 110 <SEP> 120 <SEP> 120 <SEP> 0
 <tb> 7 <SEP> 7 <SEP> 25 <SEP> 95 <SEP> 15 <SEP> 70 <SEP> 50
 <tb> 8 <SEP> 8 <SEP> 20 <SEP> 100 <SEP> 15 <SEP> 70 <SEP> 50
 <tb> 9 <SEP> 9 <SEP> 10 <SEP> 110 <SEP> 5 <SEP> 10 <SEP> 110
 <tb> 10 <SEP> 10 <SEP> 20 <SEP> 100 <SEP> 115 <SEP> 115 <SEP> 5
 <tb> 11 <SEP> sum <SEP> 315 <SEP> 885 <SEP> 545 <SEP> 800 <SEP> 400
 <tb> 12 <SEP> medium <SEP> 31.5¯6.5 <SEP> 88.5¯6.5 <SEP> 54.5¯12,

  4 <SEP> 80¯11.9 <SEP> 40¯11.3
 <tb> Animals <SEP> having <SEP> received <SEP> on <SEP> Compound <SEP> claimed <SEP> ä <SEP> the <SEP> dose <SEP> from <SEP> 5 <SEP> mg / kg
 <tb> 13 <SEP> 1 <SEP> 60 <SEP> 60 <SEP> 120 <SEP> 120 <SEP> 0
 <tb> 14 <SEP> 2 <SEP> 50 <SEP> 70 <SEP> 5 <SEP> 75 <SEP> 45
 <tb> 15 <SEP> 3 <SEP> 35 <SEP> 85 <SEP> 120 <SEP> 120 <SEP> 0
 <tb> 16 <SEP> 4 <SEP> 20 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 20
 <tb> 17 <SEP> 5 <SEP> 55 <SEP> 65 <SEP> 30 <SEP> 115 <SEP> 5
 <tb> 18 <SEP> 6 <SEP> 35 <SEP> 85 <SEP> 20 <SEP> 110 <SEP> 10
 <tb>
 

  <Desc / Clms Page number 21>

 Table 5 continued
 EMI21.1
 
 <tb>
 <tb> 19 <SEP> 7 <SEP> 15 <SEP> 105 <SEP> 45 <SEP> 60 <SEP> 60
 <tb> 20 <SEP> 8 <SEP> 60 <SEP> 60 <SEP> 75 <SEP> 75 <SEP> 45
 <tb> 21 <SEP> 9 <SEP> 30 <SEP> 90 <SEP> 55 <SEP> 100 <SEP> 20
 <tb> 22 <SEP> 10 <SEP> 40 <SEP> 80 <SEP> 120 <SEP> 120 <SEP> 0
 <tb> 23 <SEP> sum <SEP> 400

   <SEP> 800 <SEP> 690 <SEP> 995 <SEP> 205
 <tb> 24 <SEP> medium <SEP> 40 + 4, <SEP> 8 <SEP> 80 + 4, <SEP> 8 <SEP> 69 + 12, <SEP> 4 <SEP> 99, <SEP> 5 + 6, <SEP> 5 <SEP> 20, <SEP> 5 + 4, <SEP> 8
 <tb> Animals <SEP> having <SEP> received <SEP> on <SEP> Compose <SEP> claimed <SEP> to <SEP> the <SEP> dose <SEP> from <SEP> 0,

    <SEP> 5 <SEP> mg / kg
 <tb> 25 <SEP> 1 <SEP> 40 <SEP> 80 <SEP> 120 <SEP> 120 <SEP> 0
 <tb> 26 <SEP> 2 <SEP> 30 <SEP> 90 <SEP> 30 <SEP> 110 <SEP> 10
 <tb> 27 <SEP> 3 <SEP> 25 <SEP> 95 <SEP> 45 <SEP> 110 <SEP> 10
 <tb> 28 <SEP> 4 <SEP> 55 <SEP> 65 <SEP> 10 <SEP> 60 <SEP> 60
 <tb> 29 <SEP> 5 <SEP> 35 <SEP> 85 <SEP> 30 <SEP> 100 <SEP> 20
 <tb> 30 <SEP> 6 <SEP> 20 <SEP> 100 <SEP> 120 <SEP> 120 <SEP> 0
 <tb> 31 <SEP> 7 <SEP> 40 <SEP> 80 <SEP> 80 <SEP> 80 <SEP> 40
 <tb> 32 <SEP> 8 <SEP> 25 <SEP> 95 <SEP> 120 <SEP> 120 <SEP> 0
 <tb> 33 <SEP> 9 <SEP> 40 <SEP> 80 <SEP> 35 <SEP> 85 <SEP> 35
 <tb> 34 <SEP> 10 <SEP> 35 <SEP> 85 <SEP> 120 <SEP> 120 <SEP> 0
 <tb> 35 <SEP> sum <SEP> 345 <SEP> 855 <SEP> 710 <SEP> 1025 <SEP> 175
 <tb> 36 <SEP> medium <SEP> 34.5 + 2.2 <SEP> 85.5¯3.8 <SEP> 71.0¯11.9 <SEP> 102.5¯6.5 <SEP> 17.5¯3,

  8
 <tb>
 

  <Desc / Clms Page number 22>

 
The study of the pharmacological properties of the claimed compound has shown that it has a potentiating action on the serotonergic system, causes the accumulation of
 EMI22.1
 serotonin, elevates its circulation; i1 has a progressive potentiating action on the effect of Phenamine (potentiation of stereotypy) and Dopamine: it intensively restores the level of Dopamine (but not that of Noradrenaline) reduced by the administration of Reserpine . The claimed compound has an antagonistic action to that of Reserpine (it reduces hypothermia, eliminates blepharospasms) as well as that of Tetrabenazine.



   The claimed compound eliminates catalepsy caused by Naloperidol, Tetrabenazine, Reserpine. The claimed compound does not exert a significant influence on the cardiovascular responses after administration of noradrenaline, of Tyramine; he doesn't have
 EMI22.2
 cholinolytic action, it does not exert a sensitive action on the trecor dlArécoline; it has a weak anticonvulsive action antagonizing corazole. The claimed compound has no influence on the depressive reaction caused by the ingestion of Acetylcholine and by the peripheral irritation of the end of the vagus does not depress the orientation reaction, does not cause myorelaxation, the disturbance of coordination, modification of the reflex activity conditions.

  <Desc / Clms Page number 23>

 



   The restitution of the motivational activity, of the reactions linked to the impulse, to the energetic activity oriented towards the achievement of the goal is the main factor in the development of the antidepressant effect; the claimed compound eliminates confusion (embarrassment),
 EMI23.1
 apathy, stupor, indolence. It restores and increases the activity of emotional behavior, initiative and the adequacy of emotional reaction. It does not cause aggressiveness, hostility (animosity), alarm, increase in reflex activity.



   The claimed compound has a great ease of biological use (it is effective by enteral and parenteral administration). Its maximum concentration in the blood is established in 30-40 minutes. The half-destruction period is 4-6 hours. It is characterized by a rapid onset of action, a therapeutic effect after both single and repeated administration and by a large possibility of therapeutic doses. Experiments have shown that the claimed compound has a specific central action on the metabolism of ethanol.

   It has been noted that the claimed compound
 EMI23.2
 reduces the consumption level of a 15% methanol solution under conditions of free choice between a methyl alcohol solution and water. the claimed compound reduces the formation of alcoholic motivation and decreases physical dependence at the stage of its formation.



  It can be assumed that the claimed compound can be used for the pharmacotherapy of patients with chronic alcoholism outside of a period of acute abstinence. The study of

  <Desc / Clms Page number 24>

 the local action of the compound claimed in the tests on 3 types of animals has shown the absence of clinical and morphological signs of a local irritant action. Sensitizing properties have not appeared.



  The drug has not shown any embryotoxic, teratogenic or carcinogenic action. Nor is there any mutagenesis by the dominant lethality test.



   The claimed compound has been tested in clinical trials on more than 1000 patients.



  The claimed compound has been tried as an antidepressant on depressions of various etiologies and severities: - endogenous depressions with manic-depressive psychosis and various forms of schizophrenia; - senile depressions and involution; - reactive and neurotic depressions; - depressions caused by an organic brain disorder; - depressive disorders due to chronic alcoholism.



   The trials were carried out on patients (men and women) suffering from a main mental disorder of various degrees of severity with comparison with the action of a placebo and typical antidepressants. The claimed compound was used intravenously.
 EMI24.1
 usually venous or intramuscular (drip or by injection), twice a day. In the case of prolonged developed psychotic depression resistant to therapy with known antidepressants, treatment began with intravenous administration of the drug

  <Desc / Clms Page number 25>

 in an aqueous solution of sodium chloride or in an aqueous solution at 5% of glucose.

   Treatment with intravenous drip was carried out from 2 to 20 days depending on the dynamics of the depressive disorders, passing successively to intramuscular injection or taking the drug internally. The average daily doses in clinical conditions, depending on the severity of the disease, were 60 to 200 mg, the maximum doses reaching 400 mg. According to the degree of intensity of the signs of the main diagnosis, the material was classified in accordance with the glossary of positive psychological disturbances for a unified estimate of the condition of the patients during the clinical trial of the drug.

   The therapeutic action in small doses of the claimed drug made it possible to note a lesser depth of dark mood from the 2nd-3rd day, the appearance of the tendency to a certain tranquility, the decrease in irritability. In the following days, there was a slow but constant improvement in mood, an easier approach to the patient and his animation in the intellectual sphere. When the treatment was finished, the majority of patients noted a complete disappearance of the signs of depressive athology. Mental depression syndrome has been shown to be resistant to therapy with the claimed drug.

   Note that the degree of fatigue, relaxation, confusion (embarrassment) decreased during treatment, on the other hand productivity, sociability, the general estimate of adaptation increased.

  <Desc / Clms Page number 26>

 



   By generalizing the data from the therapy carried out, it can be concluded that the claimed drug is effective in patients with severe schizophrenia both in the case of developed affective states and in the case of access to the delusional affective structure. A harmonious action of the claimed drug on the regression dynamics of the analyzable depressive symptoms is characteristic, which also distinguishes it from known antidepressants (Alival, Amitryptiline). The claimed drug has no sedative component in the actual psychotropic action and has a marked progressive stimulatory effect.

   However, there have been practically no cases of reinforcement of the alarm, worsening of the state, reversal of affect (affective behavior disorder), characteristics of antidepressants which have a stimulating component.



   According to its action on affective behavior disorders, the drug claims occupies an intermediate situation between major and minor antidepressants.



   It is characteristic that the intravenous administration of the claimed drug diminishes or eliminates the serious depressive pathology resistant to the action of powerful antidepressants such as Melipramine, Amitriptiline, Ludiamyl. These data indicate the possibility of applying the claimed drug during severe non-curable (irreversible) depression.

  <Desc / Clms Page number 27>

 



   The claimed drug has a wide variety of indications and can be used in the treatment of a simple melancholic syndrome, asthenic and hypodynamic depressive conditions, depression with inhibitions of ideation and movement. It is particularly effective in the case of slowly developing depressions with manifestations of apathy, stupor, motor inhibition, reduced motivation.



   If you are in the presence of marked depressions, particularly anxiety or anxiety, delusional and hallucinatory psychoses, you should use the claimed drug in combination with neuroleptics.



   One can use the drug claimed in the treatment of alcoholism for the treatment of asthenosubdepressive states, adynamic subdepressions evolving with neurasthenia, depression, apathy, high fatigue in the absence of depression, dystrophic disorders, insomnia. The claimed drug is prescribed for patients recovering from alcoholism and outside the period of acute abstinence.



   The claimed drug can be used in various dosage forms, namely in the form of injectable solutions, tablets, suppositories, sugar and fruit syrups, starch, enemas.



   The single dose of the claimed drug used internally is 30-50 mg to 100-150 mg depending on the peculiarities of the condition and the depth of the depression. The average daily doses are 60 to 200 mg, the

  <Desc / Clms Page number 28>

 maximum doses being 400 mg. In the case of application of the medicament in the form of injectable solutions, preferably a
 EMI28.1
 0.25% solution in double-distilled water, per 2 ml in the ampoules. In the case of application in the form of injections (by syringe and drip, intravenous and intramuscular) the daily dose of the claimed drug is dissolved in 250-500 ml of isotonic sodium chloride solution, or in a solution 5% glucose.



   The treatment begins with the administration and the dose of 50 mg with subsequent increase in doses up to the valid therapeutic doses (200-250 mg).



   The medicament claimed in the form of tablets preferably contains the active principle in an amount of 0.01 g per tablet.



   The claimed drug is used internally (after a meal), intravenously or intramuscularly (by syringe or drip) twice a day (the second dose, to exclude sleep disturbance, no later than 6 p.m.). In the case of prolonged psychotic depression resistant to therapy, it is rational to start with an administration.
 EMI28.2
 intravenous nitration (drip or syringe) at a daily dose of 200-250 mg and at the initial dose of 50 mg. Continue the drip treatment for 2 to 25 days depending on the dynamics of the depressive disorder, then switch to intramuscular administration or taking the drug internally.

  <Desc / Clms Page number 29>

 



   To increase the effectiveness of therapy, it is better to use the drug intramuscularly with simultaneous prescription internally. In the case of effective therapy by intramuscular administration, the single doses may constitute 10-25 mg, the daily doses 20-25 mg.



   The side effects of the claimed drug are insignificant, which allows harmless use, including in outpatient practice.



   A short-term drop in blood pressure, the onset of a headache. feeling of a heavy head is possible during administration of high doses. It is recommended in this case to reduce the dose of the drug. In certain cases, one can note in the clinical picture the aggravation of the disorders and irritability. To prevent or eliminate these phenomena, it is advisable to combine the intake of the claimed drug with that of neuroleptics and tranquilizers.



  The use of the claimed drug is contraindicated in the case of acute inflammatory conditions of the kidneys, liver, poisoning by narcotic, hypnotic and analgesic agents, and also in the acute period of alcohol withdrawal.



   Other characteristics and advantages of the invention will be better understood on reading the description which follows of several concrete embodiments.



   Example 1

  <Desc / Clms Page number 30>

 
To a solution of 2.9 g (0.02 mole) of N- (3-aminopropyl) morpholine in 6 ml of absolute ethanol is added dropwise, with stirring and external cooling with water (8- 15 C), a fresh solution of 3.5 g (0.02 mole) of para-chlorobenzoyl chloride in 6 ml of absolute ethanol. The mixture is left for 12 hours. The precipitate formed is filtered, washed with 5 ml of absolute ethanol, dried in a vacuum desiccator, 5.7 g (90.4%) of
 EMI30.1
 para-chloro-N- (3-morpholinopropyl) benzamide hydrochloride with a melting point of 184-186 C which is recrystallized from absolute ethanol with activated charcoal.

   The target product is obtained, which is a white crystalline substance, well soluble in water, ethyl alcohol, acetone, with a melting point of 188-189 C, Rf = 0.77 (thin layer chromatography, plates Silufol, isopropanol-ethyl ether-25% aqueous ammonia in ratios of
 EMI30.2
 5: 2: 1); IR spectrum in petroleum jelly 1656 cm 1 (0C = 0), 3280 cm (J combined), 3460 cm (\.,., llbre). r) n
Example 2
To a solution of 2.9 g (0.02 mole) of N- (3-aminopropyl) morpholine in 20 ml of isopropanol is added dropwise, with stirring and external cooling with water (8-15 C), a fresh solution of 3.5 g (0.02 mole) of para-chlorobenzoyl chloride in 4 ml of isopropanol. The mixture is bandaged for 12 hours.

   The precipitate formed is filtered, washed with 5 ml of isopropanol, dried in

  <Desc / Clms Page number 31>

 a vacuum desiccator. 5.3 g (84.1%) of para-chloro-N- (3-morpholinopropyl) benzamide hydrochloride with a melting point of 181-183OC are obtained and after recrystallization an identical product
 EMI31.1
 to that obtained in Example 1.



   Example 3
A solution of 3.5 g (0.02 mode) of para-chlorobenzoyl chloride in 10 ml of dichloroethane is added dropwise, with stirring and at a reaction mixture temperature of up to 40 ° C., 2 , 9 g (0.02 ml) of N- (3-aminopropyl) morpholine in 14 ml of dichloroethane. The reaction mixture is left for one hour. The precipitate formed is filtered, washed with 5 ml
 EMI31.2
 of isopropanol, it is dried in a vacuum desiccator. 5.4 g (85.7%) of para-chloro-N- (3-morpholinopropyl) benzamide hydrochloride identical to the product obtained in Example 1 are obtained.



   Example 4
To a solution of 3.5 g (0.02 mole) of para-chlorobenzoyl chloride in 10 ml of acetone, the reaction mixture is added dropwise with stirring and at a temperature of up to 40 ° C. , 2.9 g (0.02 mole) of N- (3-aminopropyl) morpholine in 14 ml of acetone. The reaction mixture is left for one hour. The precipitate formed is filtered, washed with 5 ml of isopropanol, dried in a vacuum desiccator, 5.3 g are obtained.

  <Desc / Clms Page number 32>

 (84.1%) of para-chloro- hydrochloride - N- (3-morpholinopropyl) benzamide, identical to that obtained in Example 1.



   Example 5
To a solution of 3.5 g (0.02 mole) of para-chlorobenzoyl chloride in 10 ml of methylene chloride is added dropwise, with stirring and at a reaction mixture temperature of up to 40 ° C., 2.9 g (0.02 mole) of NO-aminopropyl) morpholine in 14 ml of methylene chloride. The reaction mixture is left for one hour. The precipitate formed is filtered, washed with 5 ml of isopropanol, dried in a vacuum desiccator, 6.0 g (95.2%) of hydrochloride are obtained
 EMI32.1
 of para-chloro-N- (3-morpholinopropyl) benzamide, identical to that obtained in Example 1.



   Example 6
To a solution of 3.5 g (0.02 mol) of para-chlorobenzoyl chloride in 10 ml of acetonitrile is added dropwise, with stirring and at a reaction mixture temperature of up to 40 ° C. , 9 g (0.02 mole) of N- (3-aminopropyl) morpholine in 14 ml of acetonitrile. The reaction mixture is left for one hour. The precipitate formed is filtered, washed with 5 ml of isopropanol, dried in a vacuum desiccator, 6.1 g (96.8%) of hydrochloride are obtained.
 EMI32.2
 para-chloro - N (3-morpholinopropyl) benzamide, - tAr-t-. t 1. <-. . tl tl. 1 tflt 1

  <Desc / Clms Page number 33>

 
EXAMPLE 7 Para-hydrochloride is obtained
 EMI33.1
 chloro-N- (3-morpholinopropyl) benzamide as in Example 1.

   Then 3.19 g (0.01 mole) of para-chloro-N- (3--morphorphopropyl) benzamide hydrochloride is treated with 0.6 g of NaOH in 40 ml of water, the product obtained is extracted with benzene, the benzene extract is dried with Magnesium sulfate, the benzene is removed, para-chloro-N (3-morpholinopropyl) benzamide is obtained, which is a crystalline substance.
 EMI33.2
 talline white, soluble in acetone, ethyl alcohol, chloroform, hardly soluble in water, with a melting point of 87-88 C, Rf = 0.77 (chromatography on thin layers on Silufol plates, isopropanol -ethyl ether-25% aqueous ammonia in a ratio of 5: 2: 1).

   The IR spectrum in petroleum jelly oil is: 1632 cm (\) c = O), 3334 cm-1
 EMI33.3
 NH'cambine; in the 1st chloroform 1661 cm (&commat; c = O, 3272 cm NHP how much6), 3453 cm NH's) '


    

Claims (9)

 EMI34.1   R E V E N D I C A T I O N S 1. Para-chloro-N- (3-morpholinopropyl) benzamide and its hydrochloride of general formula:  EMI34.2    EMI34.3  or A is hul or is absent. 2. Process for the preparation of para-chloro-N- (3-morpholinopropyl) benzamide and of its hydrochloride according to claim 1, characterized in that the N- (3-aminopropyl) morpholine is reacted with para-chlorobenzoyl chloride in a polar organic solvent which inhibits the formation of side reaction products and which is isolated  EMI34.4  the product concerned.  3. Method according to claim 2, characterized in that, as polar organic solvent, one of the bodies of the group formed by ethanol, 11isopropanol, is used,  EMI34.5  acetone, dichloroethane, chloroform, methylene chloride and acetonitrile.  4. Method according to one of claims 2 and 3 characterized in that to isolate para-chloro-N- (3-morpholinopropyl) benzamide, reacting para-chloro-N- - (3-morpholinopropyl) hydrochloride benzamide with an alkali in an aqueous medium.  5. A drug with antidepressant and psychostimulatory action, containing an active principle and a pharmaceutical excipient, characterized in that, as active principle, it contains the  EMI34.6  para-chloro-N- (3-morpholinopropyl) benzanide hydrochloride of the following formula:  EMI34.7    <Desc / Clms Page number 35> 6. Injectable medicament according to claim 5, characterized in that it contains the active substance in an amount of 0.25% by mass.  7. Medicament according to one of claims 5 and 6, characterized in that as a pharmaceutical excipient it contains as  EMI35.1  solvent for double distilled water.  8. Medicament according to claim 5, presented in the form of tablets, characterized in that it contains the active substance in an amount of 0.01 g per tablet.  9. Medicament according to one of claims 5 and 8, characterized in that it contains as pharmaceutical excipient starch or powdered sugar.